In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed

https://science.sciencemag.org/content/sci/232/4746/34.full.pdf

A receptor-mediated pathway for cholesterol homeostasis.

Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids

To revise 1998 recommendations on childhood obesity, an Expert Committee, comprised of representatives from 15 professional organizations, appointed experienced scientists and clinicians to 3 writing groups to review the literature and recommend approaches to prevention, assessment, and treatment. Because effective strategies remain poorly defined, the writing groups used both available evidence and expert opinion to develop the recommendations. Primary care providers should universally assess children for obesity risk to improve early identification of elevated BMI, medical risks, and unhealthy eating and physical activity habits. Providers can provide obesity prevention messages for most children and suggest weight control interventions for those with excess weight. The writing groups also recommend changing office systems so that they support efforts to address the problem. BMI should be calculated and plotted at least annually, and the classification should be integrated with other information such as growth pattern, familial obesity, and medical risks to assess the child’s obesity risk. For prevention, the recommendations include both specific eating and physical activity behaviors, which are likely to promote maintenance of healthy weight, but also the use of patient-centered counseling techniques such as motivational interviewing, which helps families identify their own motivation for making change. For assessment, the recommendations include methods to screen for current medical conditions and for future risks, and methods to assess diet and physical activity behaviors. For treatment, the recommendations propose 4 stages of obesity care; the first is brief counseling that can be delivered in a health care office, and subsequent stages require more time and resources. The appropriateness of higher stages is influenced by a patient’s age and degree of excess weight. These recommendations recognize the importance of social and environmental change to reduce the obesity epidemic but also identify ways healthcare providers and health care systems can be part of broader efforts.

/pdf/expert-committee-recommendations-regarding-the-prevention-38kyxmdgpa.pdf

Expert Committee Recommendations Regarding the Prevention, Assessment, and Treatment of Child and Adolescent Overweight and Obesity: Summary Report

Approximately 200 studies that examined the relationship between fruit and vegetable intake and cancers of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary are reviewed. A statistically significant protective effect of fruit and vegetable consumption was found in 128 of 156 dietary studies in which results were expressed in terms of relative risk. For most cancer sites, persons with low fruit and vegetable intake (at least the lower one-fourth of the population) experience about twice the risk of cancer compared with those with high intake, even after control for potentially confounding factors. For lung cancer, significant protection was found in 24 of 25 studies after control for smoking in most instances. Fruits, in particular, were significantly protective in cancers of the esophagus, oral cavity, and larynx, for which 28 of 29 studies were significant. Strong evidence of a protective effect of fruit and vegetable consumption was seen in cancers of the pancreas and stomach (26 of 30 studies), as well as in colorectal and bladder cancers (23 of 38 studies). For cancers of the cervix, ovary, and endometrium, a significant protective effect was shown in 11 of 13 studies, and for breast cancer a protective effect was found to be strong and consistent in a meta analysis. It would appear that major public health benefits could be achieved by substantially increasing consumption of these foods.

Fruit, vegetables, and cancer prevention: A review of the epidemiological evidence

The human diet contains a great variety of natural mutagens and carcinogens, as well as many natural antimutagens and anticarcinogens. Many of these mutagens and carcinogens may act through the generation of oxygen radicals. Oxygen radicals may also play a major role as endogenous initiators of degenerative processes, such as DNA damage and mutation (and promotion), that may be related to cancer, heart disease, and aging. Dietary intake of natural antioxidants could be an important aspect of the body’s defense mechanism against these agents. Many antioxidants are being identified as anticarcinogens. Characterizing and optimizing such defense systems may be an important part of a strategy of minimizing cancer and other age-related diseases.

https://science.sciencemag.org/content/sci/221/4617/1256.full.pdf

Dietary carcinogens and anticarcinogens Oxygen radicals and degenerative diseases

National Cholesterol Education Program

Conjugated linoleic acid and atherosclerosis in rabbits

Advances in Lipid Research

Conjugated linoleic acid is a collective term used to designate a mixture of positional and geometric isomers of linoleic acid in which the double bonds are conjugated. Unlike linoleic acid, there is a paucity of information regarding the effect of dietary conjugated linoleic acid on plasma lipoproteins and aortic atherosclerosis. Therefore, fifty hamsters were divided into five groups of ten and fed 0 (Control), 0.06 (LOW), 0.11 (MEDIUM), and 1.1 (HIGH) en% conjugated linoleic acid or 1.1 en% linoleic acid. Blood samples were taken at 4, 8 and 11 weeks for plasma lipid analyses and for plasma tocopherol assay at sacrifice. Animals fed the conjugated linoleic acid-containing diets collectively had significantly reduced levels of plasma total cholesterol, non-high density lipoprotein cholesterol, (combined very low and low density lipoprotein) and triglycerides with no effect on high density lipoprotein cholesterol, as compared to CONTROLs. Linoleic acid-fed animals relative to CONTROLs also had reduced plasma total cholesterol, non-high density lipoprotein cholesterol and triglycerides, but only the latter was statistically significant. Compared to the CONTROL group, plasma tocopherol/total cholesterol ratios determined from plasma pools for the LOW, MEDIUM and HIGH conjugated linoleic acid and linoleic acid groups were increased by 48%, 48%, 86% and 29%, respectively, suggesting a tocopherol-sparing effect, at least for the conjugated linoleic acid treatment. Morphometric analysis of aortas revealed less early atherosclerosis in the conjugated linoleic acid and linoleic acid-fed hamsters compared to the CONTROL group.

Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atherosclerosis in hypercholesterolemic hamsters.

This critical review article examines the composition and source of inulin and oligofructose, the physiological effects of their consumption, and how these materials relate to the concept of dietary fiber. Inulin and oligofructose are fructans extracted on a commercial basis from the chicory root. Inulin has been defined as a polydisperse carbohydrate material consisting mainly, if not exclusively, of beta (2-1) fructosyl-fructose links ranging from 2 to 60 units long. Native chicory inulin has an average degree of polymerization (DP) of 10 to 20, whereas oligofructose contains chains of DP 2 to 10, with an average DP of 4. While a universally accepted definition for dietary fiber does not exist, it is generally agreed that this term includes saccharides (+ lignin) that are not hydrolyzed or absorbed in the upper part of the gastrointestinal tract. These materials reach the colon, where they may be totally fermented, partially fermented, or remain unfermented. In addition, fibers contribute to fecal bulking. Inulin and oligofructose are not digested in the upper part of the gastrointestinal tract or are they absorbed and metabolized in the glycolytic pathway, or directly stored as glycogen like 'sugars' or starches. None of the molecules of fructose and glucose that form inulin and oligofructose appear in the portal blood. These materials are quantitatively fermented by the microflora of the colon; further, it has been demonstrated that this fermentation leads to the selective stimulation of the growth of the bifidobacteria population. After reviewing their chemistry, origin, and physiological effects, it is the opinion of the authors that inulin and oligofructose are dietary fiber. They share the basic common characteristics of dietary fibers, that is, saccharides of plant origin, resistance to digestion and absorption in the small intestine, and fermentation in the colon to produce short-chain fatty acids that are absorbed and metabolized in various parts of the body. Moreover, this fermentation induces a bulking effect.

David Kritchevsky

Papers

National Cholesterol Education Program

Conjugated linoleic acid and atherosclerosis in rabbits

Advances in Lipid Research

Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atherosclerosis in hypercholesterolemic hamsters.

Inulin and Oligofructose as Dietary Fiber: A Review of the Evidence